Erectile dysfunction is defined as an inability to induce and sustain penile erection adequate for sexual intercourse, or refers to a condition of the inability to enjoy satisfactory sexual life due to ejaculation disorders such as premature ejaculation and delayed ejaculation or to reach orgasm. It is known that 3 to 5% of the men between 18 and 75 years of age in the United States suffer from chronic erectile dysfunction and most of them are 55 years and older.
Drugs capable of inhibiting subtype 5 of cGMP phosphodiesterase (PDEv inhibitors) can be used for erectile dysfunction treatment. PDEv inhibitors inhibit degradation of cGMP to increase the concentration of cGMP in tissues. Increased cGMP concentration in tissues leads to relaxation of penile smooth muscle to increase the amount of blood flowing into the penile spongy tissues, thus contributing to the treatment of erectile dysfunction.
Examples of PDEv inhibitors heretofore known include vardenafil ([3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl, C23H32N6O4S, CAS No. 224785-90-4), sildenafil (1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine, C22H30N6O4S, CAS No. 171599-83-0), tadalafil (pyrazino[1′,2′1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)—, C22H19N3O4, CAS No. 171596-29-5), and udenafil, C25H36N6O4S, CAS No. 268203-93-6). vardenafil, sildenafil, tadalafil, and udenafil, together with medicinal uses thereof, are disclosed in Korean Patent Nos. 0430355, 0262926, 0357411, and 0353014, respectively. For rapid absorption and good bioavailability, such PDEv inhibitors and water soluble salts are prepared into tablets, which are currently sold as oral therapeutic agents for erectile dysfunction.
Of these PDEv inhibitors, sildenafil is a drug for the treatment of erectile dysfunction and the treatment and prophylaxis of angina and pulmonary hypertension. Sildenafil was originally developed and clinically tested as a therapeutic agent for angina. During clinical testing, sildenafil was found to be particularly effective in penile erection. Based on this finding, sildenafil was developed as a therapeutic agent for erectile dysfunction. Since approval by the United States FDA in March, 1998, sildenafil citrate has been commercialized and most widely used as a pharmaceutical drug associated with erectile dysfunction treatment. Sildenafil citrate has been sold under the trade name Viagra® tablet since October, 1999.
In many cases, sildenafil is irregularly administered just before sexual activity. In some cases, sildenafil needs to be administered urgently in unexpected situations on account of its characteristics, and it is thus preferred to carry sildenafil in a convenient manner. In view of the foregoing, attempts have been made to develop sildenafil into formulations that can be easily taken without water rather than into general tablets or capsules.
For example, Korean Patent Publication No. 2007-0100023 discloses an orally fast dissolving formulation of PDE-5 inhibitors which contains a PDEv inhibitor such as sildenafil as an active ingredient. This formulation is an orally disintegrating tablet (ODT) using a solid dispersion in which sildenafil is included in a cyclodextrin.
Korean Patent No. 627199 discloses an orally fast dissolving film (ODF) including sildenafil citrate as an active ingredient. This formulation uses a hydrocolloid as a film-forming polymer. A starch graft copolymer is used to enhance the adhesion of the film formulation to the mucosa.
On the other hand, fast dissolving films including sildenafil are readily disintegrated or dissolved in the oral cavity and can be taken even without water, thus being very useful for the elderly who suffer from difficulty in swallowing tablets or capsules, disabled children, patients lying in bed, and busy modern people. Liquid preparations can be presented as substitutes for tablets or capsules to the elderly and children. However, liquid preparations have the disadvantages of poor stability and inaccurate dose.
Particularly, absorption of a drug through the oral mucous membrane can avoid the liver first-pass effect. Therefore, fast dissolving films are novel useful formulations that can also be applied to drugs highly susceptible to hepatic metabolism among drugs absorbed from the digestive tract.
Typical film preparations are disintegrated within 1 minute and are generally processed to have a thickness of 50 to 150 μm and a size of 22 mm (width)×32 mm (length), which corresponds to an area of 7 cm2. Some film preparations may be slightly elongated in width and length. However, there has been no report on preparations having an area of 10 cm2 taking into consideration the convenience of administration to patients. Due to the limited thickness and size, currently commercially available fast dissolving film products have a weight of about 50 mg to about 150 mg per sheet.
Despite the convenience of such film preparations, the limited weight per sheet hinders the application to high-dose preparations. Gas-X Thin Strips® from Novartis is known to be the only commercially available fast dissolving film preparation that includes 50% or more of simethicone as an active ingredient. Specifically, this film preparation has a weight of 110 mg per sheet and contains 62.5 mg of the active ingredient. That is, the active ingredient accounts for 57% of the film sheet. It is generally known that an appropriate content of an active ingredient per sheet is about 30% or less. If the content of an active ingredient in a film is 30% or more, the film has poor physical properties, resulting in an increase in brittleness, and is breakable during production and distribution. These disadvantages make it difficult to commercialize the film. Gas-X Thin Strip is the only commercially available fast dissolving film preparation that includes 50% or more of the active ingredient and has relatively good resistance to brittleness.
Sildenafil citrate-containing preparations are currently sold by Pfizer under the brand name of Viagra® and are commercially available in three doses of 25 mg, 50 mg and 100 mg. In the 100 mg preparation, 100 mg of sildenafil corresponds to 140.45 mg of sildenafil citrate, which is greater than that in the currently commercially available preparation Gas-X. Accordingly, a preparation containing 50% or more of sildenafil as an active ingredient should be designed such that 100 mg of sildenafil is processed into a film preparation. For example, a film containing 50% by weight of sildenafil citrate as an active ingredient may have a weight of about 281 mg, which corresponds to a thickness of 280 μm. In this case, the physical properties and brittleness resistance of the film are considerably deteriorated due to the excessive film thickness, making it difficult to produce the film.
Coating, ion exchange resin adsorption or the use of a masking aid is further required to mask the extremely bitter taste of sildenafil citrate, which increases the thickness of the film and deteriorates the physical properties and brittleness of the film.
In an attempt to overcome such disadvantages, U.S. Patent Publication No. 2008/0220029 discloses a fast dissolving film containing an active ingredient including at least 40% of the film weight. The Examples section of this patent publication describes taste masked fast dissolving films containing previously coated active ingredients such as ibuprofen.
U.S. Patent Publication No. 2008/0233174 discloses a fast dissolving film containing at least 30% by weight of an active ingredient, based on the weight of the film. The Examples section of this patent publication describes the use of encapsulated acetaminophen. The high-dose fast dissolving film is produced after previous masking of the active ingredient through coating or encapsulation with two kinds of polymers having different glass transition temperatures. U.S. Pat. No. 6,552,024 describes a fast dissolving film containing sildenafil citrate. However, this patent fails to describe how to mask the bitter taste of sildenafil citrate as an active ingredient. An active ingredient of a fast dissolving film preparation is disintegrated or dissolved in the oral cavity on account of the characteristics of the preparation. At this time, a bitter or unpleasant taste of the active ingredient should be masked for industrial applicability of the preparation. In connection with the taste masking of a sildenafil preparation, U.S. Patent Publication No. 2009/0047330 discloses an orally fast dissolving film composition of a PDE-5 inhibitor containing a PDEv inhibitor such as sildenafil as an active ingredient. The Examples section of this patent publication describes masking of sildenafil with cyclodextrins.
Other approaches to mask inherent bitter tastes of drugs are disclosed in the literature. For example, PCT International Publication No. WO 2001/70194 discloses the production of a fast dissolving orally consumable film by adsorbing an active ingredient to an ion exchange resin as a taste masking agent. For masking the taste of the active ingredient, the resin should be used in an amount of 1 to 3 times the amount of the active ingredient, making it difficult for the fast dissolving film to include a high dose 50%) of the active ingredient. Further, PCT International Publication No. WO 2003/070227 describes the use of a carbon dioxide-forming substance such as sodium bicarbonate for taste masking. Disadvantageously, sodium bicarbonate is limited in masking a strong bitter taste of a drug.
Korean Patent Registration No. 1074271 describes a fast dissolving film using a stevioside-based sweetener and a high-potency sweetener to effectively mask an unpleasant taste. This is an attempt to suppress a bitter taste of an active ingredient using a combination of general sweetening agents but is limited in the application to a very bitter drug such as sildenafil citrate. In the Examples section of this patent document, an active ingredient is used in an amount of 0.1 to 30% by weight with respect to the weight of the film, but the use of 40% by weight or more of an active ingredient with respect to the total weight of the formulation cannot be found. U.S. Patent Publication No. 2007/0292515 discloses an approach to mask the bitter taste of ketoprofen. According to this approach, the pH of the ketoprofen is increased using an alkalizing agent such as sodium hydroxide, and the ketoprofen is then loaded in a film formulation. Korean Patent No. 354310 discloses the use of a basic buffer solution or a pH-adjusting agent to minimize the bitter taste of azithromycin. Korean Patent No. 10-1188594 discloses the use of sodium hydroxide, sodium bicarbonate or a mixture thereof to mask the bitter taste of sildenafil citrate. Korean Patent Publication No. 10-2012-0101301 discloses a technique associated with the use of a sildenafil free base. The Examples section of this patent publication describes the use of 50% or less of the active ingredient.
Based on the above, to the best of our knowledge, no report has appeared on an orally fast disintegrating film formulation with markedly improved brittleness resistance including at least 50% of sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient whose bitter taste is masked. Bitter taste masking of an active ingredient inevitably leads to poor physical properties and brittleness resistance of a film. Meanwhile, good physical properties of a film indicate the presence of a small dose of an active ingredient in the film. Therefore, it is difficult to produce a fast dissolving film formulation containing Viagra 100 mg currently available in the market.